Suspensions of micronized fenofibrate

ABSTRACT

The invention provides suspensions of micronized fenofibrate in solutions comprising hydrophilic polymers and, optionally, surfactants.

RELATED APPLICATIONS

[0001] This application is a continuation of U.S. application Ser. No.10/288,425 filed Nov. 6, 2002; which is a continuation of U.S.application Ser. No. 10/126,875 filed Apr. 22, 2002, issued as U.S. Pat.No. 6,589,552; which is a continuation of U.S. application Ser. No.10/078,500 filed Feb. 21, 2002, issued as U.S. Pat. No. 6,596,317; whichis a continuation of U.S. application Ser. No. 09/899,026 filed Jul. 6,2001; which is a continuation of U.S. application Ser. No. 09/572,330filed May 18, 2000, issued as U.S. Pat. No. 6,277,405; which is acontinuation of U.S. application Ser. No. 09/005,128 filed Jan. 9, 1998,issued as U.S. Pat. No. 6,074,670; which claims priority to FrenchApplication No. 97 00 479 filed Jan. 17, 1997. This application is alsoa continuation of U.S. application Ser. No. 10/290,333 filed Nov. 8,2002.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to a novel pharmaceuticalcomposition having high bioavailability through improved dissolution,and a method for preparing it. The invention more particularly relatesto a pharmaceutical composition for administration by oral route,containing an active ingredient of poor aqueous solubility.

[0003] Numerous active ingredients suffer from the disadvantage of beingpoorly soluble in an aqueous medium, thus having an insufficientdissolution profile and, consequently, poor bioavailability within theorganism, following oral administration. The therapeutic dose requiredto be administered must thus be increased in order to obviate thisdisadvantage. This particularly applies to numerous hypolipemiant activeingredients, such as those belonging to the fibrate family.

[0004] Fenofibrate is a well-known hypolipemiant from the family offibrates, which is commercially available in various doses (100 and 300mg for example Secalip®) but in a form leading to poor bioavailabilityof the active ingredient. Indeed, due to it poor hydrosolubility,fenofibrate is poorly absorbed in the digestive tract and consequentlyits bioavailability is incomplete, irregular and often varies from oneperson to another.

[0005] To improve the dissolution profile of fenofibrate and itsbioavailability, thereby reducing the dose requiring to be administered,it would be useful to increase its dissolution so that it could attain alevel close to 100%.

[0006] Moreover, for patient comfort, it is advantageous to seek adosage form that only requires the medicament to be taken once dailywhile giving the same effect as one administered several times daily.

[0007] EP-A-0330532 discloses a method for improving bioavailability offenofibrate. This patent describes the effect of co-micronizingfenofibrate with a surfactant, for example sodium laurylsulfate in orderto improve fenofibrate solubility and thereby increase itsbioavailability. This patent teaches that co-micronizing fenofibratewith a solid surfactant improves fenofibrate bioavailability to a muchgreater extent than the improvement that would be obtained either byadding a surfactant, or through solely micronizing the fenofibrate, or,yet again, through intimately mixing the fenofibrate and surfactant,micronized separately. The dissolution method employed is theconventional rotating blade technique (European Pharmacopoeia): productdissolution kinetics are measured in a fixed volume of the dissolutionmedium, agitated by means of a standardized device; a test was alsocarried out with an alternative technique to the European Pharmacopoeia,using the continuous-flow cell method.

[0008] The process of EP-A-0330532 leads to a new dosage form in whichthe active ingredient, co-micronized with a solid surfactant, hasimproved fenofibrate dissolution, and thus increased bioavailability,which makes it possible, for a given level of effectiveness, to decreasethe daily dose of the medicament: respective 67 mg and 200 mg instead of100 mg and 300 mg.

[0009] However, the preparation method in that patent is not completelysatisfactory inasmuch as it does not lead to complete bioavailability ofthe active ingredient, and suffers from several disadvantages. Thetechnique of co-micronizing fenofibrate with a solid surfactant does, itis true, improve dissolution of the active ingredient, but thisdissolution remains, however, incomplete.

[0010] There is thus a need to improve fenofibrate bioavailability inorder to attain, over very short periods of time, a level close to 100%(or, in any case, better than the following limits: 10% in 5 minutes,20% in 10 minutes, 50% in 20 minutes and 75% in 30 minutes in a mediumconsisting of 1200 ml water to which 2% Polysorbate 80 is added, or of1000 ml of water to which 0.025M sodium lauryl sulfate sodium is added,with a blade rotation speed of 75 rpm), and this even when dissolutionmedia having a low surfactant content are used.

[0011] Applicant has found that, surprisingly, it is possible to resolvethis problem by a new method for preparing a pharmaceutical compositionby spraying a suspension of the active ingredient onto an inerthydrosoluble carrier. The present invention also relates topharmaceutical compositions thus prepared.

[0012] The use is already known of a polymer, such aspolyvinylpyrrolidone for producing tablets, in concentrations of theorder of 0.5 to 5% by weight, at a maximum 10% by weight. In this case,the polyvinylpyrrolidone is used as a binder. Similarly, the use of apolymer such as hydroxymethylpropylmethyl cellulose as a granulationbinder is known. Thus, European patent application 0,519,144 disclosespellets of a poorly soluble substance, omeprazole, obtained by sprayinga dispersion or suspension of the active ingredient in a solutioncontaining said polymer onto inert pellets in a fluidized-bedgranulator. However, here again, the polymer (HPMC and HPC) is only usedas a granulation binder, in an amount of about 50% by weight, based onthe weight of the active ingredient, which, bearing in mind the presenceof the inert pellets of a large size (about 700 μm) and the overallfinal weight leads to final active ingredient and polymer contents whichare very low, of the order of barely a few percent based on the weightof the final covered pellet. Finally, it will be noted that the size ofthe inert pellets in this documents is fairly large, which, in the caseof fenofibrate, would lead to a final formulation having a volume whichis much too large for ready oral administration.

[0013] The use of polymer, such as polyvinylpyrrolidone formanufacturing “solid dispersions” is also known, obtained in general byco-precipitation, co-fusion or liquid-phase mixing followed by drying.What we have here is fixation of the active ingredient in isolatedmicroparticles on the polyvinylpyrrolidone, which avoids problems ofpoor wetting of the solid and re-agglomeration of the particles. Thearticle “Stable Solid Dispersion System Against Humidity” by Kuchiki etal., Yakuzaigaku, 44 No. 1, 31-37 (1984) describes such a technique forpreparing solid dispersions using polyvinylpyrrolidone. The amounts ofPVP here are very high, and the ratio between the active ingredient andPVP are comprised between 1/1 and 1/20. In the case however there is noinert carrier.

[0014] WO-A-96 01621 further discloses a sustained release composition,comprising an inert core (silica in all examples) coated with a layerwhich contains the active ingredient in admixture with a hydrophilicpolymer, the weight ratio active ingredient/polymer being comprisedbetween 10/1 and 1/2 and the weight ratio active ingredient/inert corebeing comprised between 5/1 and 1/2, with an outer layer to impart thesustained release property. These compositions can be compressed. Thehydrophilic polymer can be polyvinylpyrrolidone. This document alsodiscloses a process for preparing said composition; for example in afluidized-bed granulator one will spray a dispersion of activeingredient in a polymer solution onto the inert cores. This documentsolely relates to sustained release compositions, the technical problemto be solved being the compression, without damages, of the outer layerimparting the sustained release property.

[0015] Nevertheless, nothing in the state of the art teaches nor suggestthe present invention.

SUMMARY OF THE INVENTION

[0016] Thus, the present invention provides an immediate-releasefenofibrate composition comprising:

[0017] (a) an inert hydrosoluble carrier covered with at least one layercontaining a fenofibrate active ingredient in a micronized form having asize less than 20 μm, a hydrophilic polymer and, optionally, asurfactant; said hydrophilic polymer making up at least 20% by weight of(a); and

[0018] (b) optionally one or several outer phase(s) or layer(s).

[0019] In one embodiment, a surfactant is present with the activeingredient and the hydrophilic polymer.

[0020] The invention also provides a composition comprising fenofibratehaving a dissolution of at least 10% in 5 minutes, 20% in 10 minutes,50% in 20 minutes and 75% in 30 minutes, as measured using the rotatingblade method at 75 rpm according to the European Pharmacopoeia, in adissolution medium constituted by water with 2% by weight polysorbate 80or in a dissolution medium constituted by water with 0.025M sodiumlauryl sulfate.

[0021] A method for preparing a pharmaceutical composition is alsoprovided, comprising the steps of:

[0022] (a) preparing a fenofibrate suspension in micronized form with aparticle size below 20 μm, in a solution of hydrophilic polymer and,optionally surfactant;

[0023] (b) applying the suspension from step (a) to an inerthydrosoluble carrier;

[0024] (c) optionally, coating granules thus obtained with one orseveral phase(s) or layer(s).

[0025] Step (b) is preferably carried out in a fluidized-bed granulator.

[0026] The method can comprise a step in which products obtained fromstep (b) or (c) are compressed, with or without additional excipients.

[0027] The invention also provides a suspension of fenofibrate inmicronized form having a size less than 10 μm, in a solution ofhydrophilic polymer and, optionally, surfactant.

[0028] The invention will be described in more detail in the descriptionwhich follows, with reference to the attached drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0029]FIG. 1 is a graph of a comparative study of the dissolutionprofile of a composition according to the invention, compared to that ofLipanthyl® 200M;

[0030]FIG. 2 is a graph illustrating a comparative study of thedissolution profile of a composition according to the invention and thatof pharmaceutical products commercially available on the German market.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0031] The expression “in micronized form” in this invention means asubstance in a particulate form, the dimensions of the particles beingless than or equal to about 20 μm.

[0032] Advantageously, this dimension is less than or equal to 10 μm.

[0033] In the framework of this invention, the expression “inerthydrosoluble carrier” means any excipient, generally hydrophilic,pharmaceutically inert, crystalline or amorphous, in a particulate form,not leading to a chemical reaction under the operating conditionsemployed, and which is soluble in an aqueous medium, notably in agastric acid medium. Examples of such excipients are derivatives ofsugars, such as lactose, saccharose, hydrolyzed starch (maltodextrine),etc. Mixture are also suitable. The individual particle size of theinert hydrosoluble carrier can be, for example, between 50 and 500micron.

[0034] The expression “hydrophilic polymer” in the invention should betaken to mean any high molecular weight substance (greater, for example,than 300) having sufficient affinity towards water to dissolve thereinand form a gel. Examples of such polymers are polyvinylpyrrolidone,poly(vinyl alcohol), hydroxypropylcellulose, hydroxymethylcellulose,hydroxypropylmethylcellulose, gelatin, etc. Polymer blends are alsosuitable.

[0035] The preferred hydrophilic polymer is polyvinylpyrrolidone (PVP).The PVP used in this invention has, for example, a molecular weightcomprised between 10,000 and 100,000, preferably for example between20,000 and 55,000.

[0036] The term “surfactant” is used in its conventional sense in thisinvention. Any surfactant is suitable, whether it be amphoteric,non-ionic, cationic or anionic. Examples of such surfactants are: sodiumlauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate oranother ester of polyoxyethylene sorbitane, sodium dioctylsulfosuccinate(DOSS), lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol,polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides,poloxamer®, etc. Mixtures of surfactants are also suitable.

[0037] The preferred surfactant is sodium laurylsulfate, which can beco-micronized with fenofibrate.

[0038] The compositions according to the invention can additionallycontain any excipient conventionally used in the pharmaceutical andchemical fields which is compatible with the active ingredient, such asbinders, fillers, pigments, disintegrating agents, lubricants, wettingagents, buffers, etc. As examples, excipients able to be used in thisinvention we can cite: microcrystalline cellulose, lactose, starch,colloidal silica, talc, glycerol esters, sodium stearyl fumarate,titanium dioxide, magnesium stearate, stearic acid, cross-linkedpolyvinyl pyrrolidone (AC DI SOL®), carboxymethyl starch (Explotab®,Primojel®), hydroxypropylcellulose, hydroxymethylcellulose,hydroxypropylmethylcellulose, gelatin, etc.

[0039] Here, the expression “outer phase or layer” should be taken tomean any coating on the element (a) with the active ingredient (forminga “core”). Indeed, it can be useful to have available one or severalphase(s) or layer(s) on top of the coated core. The invention thuscovers a single core with one layer, but also several cores in a phase,as is the case of tablets which are formed from “cores” mixed with aphase.

[0040] This outer layer comprises conventional excipients.

[0041] It is also possible to provide a layer comprising additives, forthe manufacture of tablets. In this embodiment, the outer layercomprises a disintegration agent and, for example, a lubricant; the thuscovered and mixed granules can then be readily compressed and easilydisintegrate in water.

[0042] The compositions according to the invention comprise, in general,based on the total composition weight excluding the outer phase orlayer, an inert hydrosoluble carrier making up from 10 to 80% by weight,preferably 20 to 50% by weight, the fenofibrate representing from 5 to50% by weight, preferably from 20 to 45% by weight, the hydrophilicpolymer representing from 20 to 60% by weight, preferably 25 to 45% byweight, the surfactant making up from 0 to 10% by weight, preferably 0.1to 3% by weight.

[0043] The outer layer or phase if present, can make up to 80% by weightof the total weight, preferably up to 50% by weight.

[0044] The hydrophilic polymer represents preferably more than 25% byweight, based on the weight of (a).

[0045] The weight ratio of fenofibrate/hydrophilic polymer can forexample be comprised between 1/10 and 4/1, preferably, for example,between 1/2 and 2/1.

[0046] When a surfactant is employed, the weight ratiosurfactant/hydrophilic polymer can be comprised for example between1/500 and 1/10, preferably, for example, between 1/100 and 5/100.

[0047] In one embodiment, the composition according to the inventiontakes the form of tablets.

[0048] This tablet preferably results from the compression of elements(a) (under the form of granules) together with an outer phase.

[0049] In another embodiment, the composition of the invention takes theform of granules enclosed inside a capsule, for example in gelatin, orinside a bag.

[0050] The compositions of the invention are particularly suitable foradministering active ingredients by oral route.

[0051] The composition according to the invention is prepared by a novelprocess comprising spraying a suspension of the active ingredient in amicronized form in a solution of a hydrophilic polymer and, optionally,a surfactant, onto the inert core.

[0052] When a surfactant is present, the active ingredient can beco-micronized with the surfactant. One will then use with advantage theteachings of EP-A-0330532.

[0053] The method according to the invention consists in using thefluidized bed granulation principle, but with specific startingmaterials, in order to arrive at an improved dissolution profile andthus, at elevated bioavailability. In particular, the invention employsa suspension of the micronized active ingredient in a solution of ahydrophilic polymer and, optionally, a surfactant.

[0054] The fluidized-bed granulation technique is widely used in thepharmaceutical industry for preparing capsules or tablets.Conventionally, according to the prior art, a powder or a mixture ofpowders (active ingredient+excipients) is put into suspension in thefluidized bed in a granulator, and a solution containing a binder and,optionally, a surfactant, is sprayed onto this bed to form granules. Thefluidized-bed granulation technique is well known to those skilled inthe art and reference should be made to standard works such as forexample “Die Tablette”, by Ritschel, Ed. Cantor Aulendorf, pages211-212.

[0055] The invention, as has been indicated, comprises spraying asuspension of an active ingredient micronized with a hydrophilic polymeronto an inert carrier. Following granulation, the granulate formedconsists of crystals of, for example, lactose, which are isolated (orpossibly agglomerated together by the spray solution) and particles ofactive ingredient and PVP adhering to the crystal surface. The granulecould similarly be constituted of coated crystals which areagglomerated, or even of such an agglomerate having received a coating.

[0056] The compositions according to the invention can also be preparedby other methods, for example by spraying a solution of the micronizedactive ingredient onto the hydrosoluble inert carrier.

[0057] The granulates thus obtained can, if desired, be provided with anouter coating or compressed into tablets, or form agglomerates.

[0058] The outer layer or layer is/are applied using conventionalcoating techniques such as coating in a pan or fluidized bed coater.

[0059] When the granulate obtained (whether subsequently coated or not)is compressed to form tablets, this step can be implemented using anyconventional technique which is suitable, for example using analternating or rotating compressing equipment.

[0060] The significant starting product is the suspension of the activeingredient. This suspension is prepared by putting the micronized activeingredient into suspension in a solution comprising the hydrophilicpolymer and, optionally, a surfactant, in solution in a solvent. If asurfactant is employed, it is put into solution in the solvent(beaker+magnetic or vane stirrer). Next, the hydrophilic polymer (PVP)is dispersed, while stirring, in the solution previously obtained.Depending on polymer solubility, this either dissolves in the solutionor forms a gel or a suspension having varying degrees of thickness.While still stirring, the micronized active ingredient is dispersed inthe form of a fine shower into the above solution or suspension, to forma homogeneous suspension. The order of these steps can be reversed. Thesolvent employed can be aqueous or organic (for example ethanol). Forexample demineralized water can be used.

[0061] The active ingredient concentration in the suspension is from 1to 40% by weight, preferably from 10 to 25%.

[0062] The hydrophilic polymer concentration in the suspension is from 5to 40% by weight, preferably 10 to 25%.

[0063] The surfactant concentration in the suspension is from 0 to 10%by weight, preferably below 5%.

[0064] The invention also covers this novel suspension.

[0065] Without wishing to be tied down to a specific theory, applicantbelieves that this novel method, through the use of a micronized activeingredient suspension in a hydrophilic polymer solution, enabled a novelcomposition to be obtained in which the active ingredient is in anon-re-agglomerated form.

[0066] The following examples illustrate the invention without limitingit.

EXAMPLE 1

[0067] Preparation of a pharmaceutical composition of fenofibrateaccording to the invention.

[0068] A composition containing, as the element a), micronizedfenofibrate, Plasdone®, Capsulac® and sodium lauryl sulfate wasprepared.

[0069] The micronized fenofibrate had a particle size of about 5 μm, asmeasured using a Coulter counter.

[0070] The Plasdone K25® corresponds to a polyvinylpyrrolidone PVP ISPand the Capsulac 60° corresponds to a coarse crystal lactose monohydrate(Meggle) (particle size between 100 and 400 μm).

[0071] The sodium laurylsulfate (7 g) is dissolved in water(demineralized water, 1750 g) and the micronized fenofibrate (350 g) isput into suspension in the mixture obtained (for example using a helixstirrer at 300 rpm for 10 minutes, then using an Ultra Turrax agitatorat 10,000 rpm, for 10 minutes). Following this, the PVP (350 g) is addedwhile still agitating, stirring (helix stirrer) being continued untilthe latter had dissolved (30 minutes). It is all passed through a sieve(350 μm) to eliminate possible agglomerates.

[0072] Separately, the lactose (400 g) is put into suspension in afluidized air bed granulator (of the Glatt® GPCG1—Top Spray type orequivalent) and heated to a temperature of 40° C.

[0073] The fenofibrate suspension is sprayed onto the lactose. This stepis carried out under the following conditions: spraying pressure: 2.1bar, air throughput 70 ³/h, air inlet temperature: 45° C.; air outlettemperature: 33° C.; product temperature 34° C.; duration of spraying: 3h.

[0074] The granulate thus obtained can be put inside capsules ortransformed into tablets. Any suitable conventional technique forpreparing such dosage forms can be used.

[0075] For transformation to tablet form, one will mix 191 g of thegranulate obtained (using for example a mixer-grinder type mixingapparatus, a planetary mixer or turn-over mixer), with the outer phasehaving the following composition:

[0076] 56 g Polyplasdone XL® (cross-linked polyvinylpyrrolidone ISP, asdescribed in the USA Pharmacopoeia “USP-NF” under the name ofcrospovidone, mean molecular weight>1,000,000);

[0077] 88 g Avicel® PH200 (microcrystalline cellulose);

[0078] 3.5 g sodium stearyl fumarate (Mendell, U.S. A.); and

[0079] 2 g Aerosil® 200 (colloidal silica).

[0080] The cross-linked polyvinylpyrrolidone, the microcrystallinecellulose, the sodium stearyl fumarate and the colloidal silica arerespectively, disintegration agents, binders, lubricating and flowenhancing agents.

[0081] The tablet can be obtained on an alternating compression machine(for example Korsch EKO) or a rotary machine (for example Fette Perfecta2).

[0082] One thus obtains tablets having the following composition,expressed in mg:

[0083] element (a): micronized fenofibrate 100.0 PVP 100.0 Lactose 114.3sodium laurylsulfate 2.0

[0084] outer phase (or layer): cross-linked PVP 92.7 microcrystallinecellulose 145.7 sodium stearyl fumarate 5.8 colloidal silica 3.3

EXAMPLE 2

[0085] Dissolution of a composition according to the invention and acomposition according to the prior art.

[0086] a) Dissolution Medium and Procedure for Measuring Dissolution.

[0087] A dissolution medium which is discriminating, in other words onein which two products having very different dissolution profiles ingastric juices will have very different dissolution curves is lookedfor.

[0088] For this, an aqueous medium containing a surfactant, this beingPolysorbate 80 (polyoxyethylene sorbitane mono-oleate) is used. Thissurfactant is readily available from various suppliers, is the object ofa monograph in the Pharmacopoeias, and is thus easy to implement (beingalso a water-soluble liquid product). Other surfactants can also beused.

[0089] The rotating blade method (European Pharmacopoeia) is used underthe following conditions: volume of medium: 1200 ml; medium temperature:37° C.; blade rotation speed: 75 rpm; samples taken: every 2.5 minutes.Determination of the amount dissolved is carried out byspectrophotometry. Test are repeated 6 times over.

[0090] b) Results

[0091] The composition according to the invention consisted of twotablets containing about 100 mg fenofibrate prepared according toExample 1.

[0092] The prior art composition was Lipanthyl® 200M from LaboratoiresFournier, containing 200 mg fenofibrate (corresponding to capsules of200 mg fenofibrate, co-micronized with sodium laurylsulfate, andcontaining lactose, pre-gelatinized starch, cross-linkedpolyvinylpyrrolidone and magnesium stearate, in line with the teachingsof EP-A-0330532).

[0093] The results obtained are shown graphically in FIG. 1, on whichthe percentage of dissolution is shown, the observed standard deviationbeing indicated between brackets.

[0094] These results clearly show that the compositions according to theinvention have a dissolution profile which is distinctly better thanthat of the prior art compositions.

[0095] These results also clearly show that with the compositions of theinvention, the standard deviation observed is distinctly lower than isthe case with prior art compositions.

EXAMPLE 3

[0096] Study of bioavailability of compositions according to theinvention and prior art compositions.

[0097] A test of bioavailability on healthy volunteers was carried out.

[0098] The following compositions were tested:

[0099] composition according to the invention: capsules containinggranules prepared according to example 1, containing 200 mg fenofibrate.

[0100] first composition according to the prior art: Lipanthyl® 200Mfrom Laboratoires Fournier, containing 200 mg fenofibrate, identical tothat in the previous example.

[0101] second prior art composition: Secalip® in capsule form (300 mgfenofibrate in the form of three 100 mg capsules).

[0102] The study was carried out on 6 healthy volunteers receiving asingle dose of fenofibrate, with a minimum 6-day rest period betweenadministrations. The samples for pharmaco-kinetic analysis werecollected after each administration at the following times: 0.5 h; 1 h;2 h; 3 h; 4 h; 5 h; 6 h; 8 h; 10 h; 12 h; 24 h; 36 h; 48 h; 72 h; and 96hours following administration of the medicament. Fenofibric acidcontent in plasma was measured for each sample.

[0103] The results obtained are given in table 1 below. TABLE 1 doseCmax tmax AUC 0-t AUC 0-∞ Product (mg) (μg/ml) (h) t½ (h) (μg · h/ml)(μg · h/ml Invention 200 5.4 6 23 148 162 Secalip ® 3 × 100 1.1 25 39 5356 100 Lipanthyl ® 200 1.6 8.3 41 71 92 200 M

[0104] The results clearly show that the compositions of the presentinvention have a dissolution profile that is an improvement overcompositions of the prior art, leading to a considerably enhancedbioavailability of the active ingredient compared to that obtained withcompositions of the prior art.

EXAMPLE 4

[0105] Comparison of the dissolution profile of compositions accordingto the invention and that of products currently on the German market.

[0106] On the German market, immediate or sustained-release fenofibrateformulations exist. Like in France, the 100 mg and 300 mg (conventional)forms coexist with 67 and 200 mg forms (having enhanced bioavailability,according to the teaching of EP-A-0330532). These products are asfollows:

[0107] Fenofibrate—ratiopharm; Ratiopharm—Ulm;

[0108] Capsules;

[0109] Composition: 100 mg fenofibrate;

[0110] Excipients: lactose, corn starch, magnesium stearate, E 171colorant, gelatine.

[0111] Durafenat; Durachemie—Wolfratshausen Capsules;

[0112] Composition: 100 mg fenofibrate;

[0113] Excipients: lactose, corn starch, magnesium stearate, E 171colorant, gelatine.

[0114] Normalip pro; Knoll—Ludwigshafen;

[0115] Capsules;

[0116] Composition: 200 mg Fenofibrate;

[0117] Excipients: Crospovidone, gelatine, monohydrate lactose,magnesium stearate, corn starch, sodium laurylsulfate, E 132 and E 171colorants.

[0118] A comparison was made between:

[0119] the tablet of the invention as prepared using example 1 (2×100mg)

[0120] Normalip pro® (200 mg);

[0121] Lipanthyl® 200M (200 mg) (according to the preceding example);

[0122] Fenofibrate by Ratiopharm® (2×100 mg);

[0123] Durafenat® (2×100 mg)

[0124] The tests were implemented under the same conditions as in theprevious examples. FIG. 2 summarizes the results.

[0125] These results clearly show that the compositions of the inventionhave a distinctly improved dissolution compared to prior artcompositions.

[0126] Obviously, the present invention is not limited to theembodiments described but may be subject to numerous variations readilyaccessible to those skilled in the art.

What is claimed is:
 1. A suspension of micronized fenofibrate in asolution of at least one hydrophilic polymer, wherein the weight ratioof fenofibrate/hydrophilic polymer is between 1/10 and 4/1.
 2. Thesuspension according to claim 1, wherein the weight ratio offenofibrate/hydrophilic polymer is between 1/2 and 2/1.
 3. Thesuspension according to claim 1, wherein the fenofibrate has a size lessthan 20 μm.
 4. The suspension according to claim 1, wherein thefenofibrate is present in an amount from 1 to 40% by weight.
 5. Thesuspension according to claim 4, wherein the fenofibrate is present inan amount from 10 to 25% by weight.
 6. The suspension according to claim1, wherein the hydrophilic polymer is present in an amount from 5 to 40%by weight.
 7. The suspension according to claim 6, wherein thehydrophilic polymer is present in an amount from 10 to 25% by weight. 8.The suspension according to claim 1, wherein the hydrophilic polymer isa polyvinylpyrrolidone, a poly(vinyl alcohol), a hydroxypropylcellulose,a hydroxymethylcellulose, a hydroxypropylmethylcellulose, a gelatin, ora mixture of two or more thereof.
 9. The suspension according to claim8, wherein the hydrophilic polymer is a polyvinylpyrrolidone.
 10. Thesuspension according to claim 1, further comprising at least onesurfactant.
 11. The suspension according to claim 10, wherein thesurfactant is present in an amount up to 10% by weight.
 12. Thesuspension according to claim 11, wherein the surfactant is present inan amount up to 5% by weight.
 13. The suspension according to claim 10,wherein the weight ratio of surfactant/hydrophilic polymer is between1/500 and 1/10.
 14. The suspension according to claim 13, wherein theweight ratio of surfactant/hydrophilic polymer is between 1/100 and5/100.
 15. The suspension according to claim 10, wherein the surfactantis sodium lauryl sulfate, monooleate, monolaurate, monopalmitate,monostearate or another ester of polyoxyethylene sorbitane, sodiumdioctylsulfosuccinate, lecithin, stearylic alcohol, cetostearylicalcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fattyacid glycerides, poloxamer, or a mixture of two or more thereof.
 16. Thesuspension according to claim 15, wherein the surfactant is sodiumlauryl sulfate.
 17. The suspension according to claim 10, wherein thefenofibrate and surfactant are co-micronized.
 18. The suspensionaccording to claim 1, wherein the hydrophilic polymer and surfactant aredissolved in the solution.
 19. A suspension of micronized fenofibrate ina solution of at least one hydrophilic polymer, wherein the weight ratioof fenofibrate/hydrophilic polymer is between 1/2 and 2/1, saidhydrophilic polymer being polyvinylpyrrolidone.
 20. The suspensionaccording to claim 19, further comprising at least one surfactant. 21.The suspension according to claim 20, wherein the weight ratio ofsurfactant/hydrophilic polymer is between 1/500 and 1/10.
 22. Thesuspension according to claim 20, wherein the surfactant is sodiumlauryl sulfate.
 23. The suspension according to claim 19, wherein thehydrophilic polymer and surfactant are dissolved in the solution.
 24. Asuspension of micronized fenofibrate in a solution of at least onehydrophilic polymer and at least one surfactant.
 25. The suspensionaccording to claim 24, wherein the weight ratio ofsurfactant/hydrophilic polymer is between 1/500 and 1/10.
 26. Thesuspension according to claim 25, wherein the weight ratio ofsurfactant/hydrophilic polymer is between 1/100 and 5/100.
 27. Thesuspension according to claim 24, wherein the surfactant is present inan amount up to 10% by weight.
 28. The suspension according to claim 27,wherein the surfactant is present in an amount up to 5% by weight. 29.The suspension according to claim 24, wherein the surfactant is sodiumlauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate oranother ester of polyoxyethylene sorbitane, sodiumdioctylsulfosuccinate, lecithin, stearylic alcohol, cetostearylicalcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fattyacid glycerides, poloxamer, or a mixture of two or more thereof.
 30. Thesuspension according to claim 29, wherein the surfactant is sodiumlauryl sulfate.
 31. The suspension according to claim 24, wherein thefenofibrate and surfactant are co-micronized.
 32. The suspensionaccording to claim 24, wherein the weight ratio offenofibrate/hydrophilic polymer is between 1/10 and 4/1.
 33. Thesuspension according to claim 32, wherein the weight ratio offenofibrate/hydrophilic polymer is between 1/2 and 2/1.
 34. Thesuspension according to claim 24, wherein the fenofibrate has a sizeless than 20 μm.
 35. The suspension according to claim 24, wherein thefenofibrate is present in an amount from 1 to 40% by weight.
 36. Thesuspension according to claim 35, wherein the fenofibrate is present inan amount from 10 to 25% by weight.
 37. The suspension according toclaim 24, wherein the hydrophilic polymer is present in an amount from 5to 40% by weight.
 38. The suspension according to claim 37, wherein thehydrophilic polymer is present in an amount from 10 to 25% by weight.39. The suspension according to claim 24, wherein the hydrophilicpolymer is a polyvinylpyrrolidone, a poly(vinyl alcohol), ahydroxypropylcellulose, a hydroxymethylcellulose, ahydroxypropylmethylcellulose, a gelatin, or a mixture of two or morethereof.
 40. The suspension according to claim 39, wherein thehydrophilic polymer is a polyvinylpyrrolidone.
 41. The suspensionaccording to claim 24, wherein the hydrophilic polymer and surfactantare dissolved in the solution.
 42. A suspension of micronizedfenofibrate in a solution of at least one hydrophilic polymer and atleast one surfactant, said hydrophilic polymer beingpolyvinylpyrrolidone and said surfactant being sodium lauryl sulfate,and the weight ratio of surfactant/hydrophilic polymer being between1/500 and 1/10.
 43. The suspension according to claim 42, wherein theweight ratio of fenofibrate/hydrophilic polymer is between 1/10 and 4/1.44. The suspension according to claim 43, wherein the weight ratio offenofibrate/hydrophilic polymer is between 1/2 and 2/1.
 45. Thesuspension according to claim 42, wherein the fenofibrate has a sizeless than 20 μm.
 46. The suspension according to claim 42, wherein thehydrophilic polymer and surfactant are dissolved in the solution.
 47. Asuspension of micronized fenofibrate in a solution ofpolyvinylpyrrolidone and of sodium lauryl sulfate, wherein the weightratio of fenofibrate/polyvinylpyrrolidone is between 1/2 and 2/1 and theweight ratio of sodium lauryl sulfate/polyvinylpyrrolidone being between1/500 and 1/10.
 48. The suspension according to claim 47, wherein thefenofibrate has a size less than 20 μm.
 49. The suspension according toclaim 47, wherein the fenofibrate is present in an amount from 1 to 40%by weight.
 50. The suspension according to claim 49, wherein thefenofibrate is present in an amount from 10 to 25% by weight.
 51. Thesuspension according to claim 47, wherein the hydrophilic polymer ispresent in an amount from 5 to 40% by weight.
 52. The suspensionaccording to claim 51, wherein the hydrophilic polymer is present in anamount from 10 to 25% by weight.
 53. The suspension according to claim47, wherein the surfactant is present in an amount up to 10% by weight.54. The suspension according to claim 53, wherein the surfactant ispresent in an amount up to 5% by weight.
 55. The suspension according toclaim 47, wherein the fenofibrate and surfactant are co-micronized. 56.The suspension according to claim 47, wherein the hydrophilic polymerand surfactant are dissolved in the solution.
 57. The suspensionaccording to claim 1, wherein the fenofibrate has a size less than 10μm.
 58. The suspension according to claim 19, wherein the fenofibratehas a size less than 10 μm.
 59. The suspension according to claim 24,wherein the fenofibrate has a size less than 10 μm.
 60. The suspensionaccording to claim 42, wherein the fenofibrate has a size less than 10μm.
 61. The suspension according to claim 47, wherein the fenofibratehas a size less than 10 μm.